Utilization of CD39 and CD103 for identification of human tumor reactive T cells for treatment of cancer

Abstract

Methods are disclosed for treating a subject with a tumor. These methods include administering to the subject a therapeutically effective amount of CD8+CD39+CD103+ T cells. Methods also are disclosed for isolating a nucleic acid encoding a T cell receptor (TCR) that specifically binds a tumor cell antigen. These methods include isolating CD8+CD39+CD103+ T cells from a sample from a subject with a tumor expressing the tumor cell antigen, and cloning a nucleic acid molecule encoding a TCR from the CD8+CD39+CD103+ T cells. In addition, methods are disclosed for expanding CD8+CD39+CD103+ T cells. In additional embodiments, methods are disclosed for determining if a subject with a tumor will respond to a checkpoint inhibitor. The methods include detecting the presence of CD8+CD39+CD103+ T cells in a biological sample from a subject.

We claim: 
     
       1. A method of treating a subject with a tumor, comprising administering to the subject a therapeutically effective amount of CD8 + CD39 + CD103 +  T cells, thereby treating the subject with the tumor. 
     
     
       2. The method of  claim 1 , further comprising administering a therapeutically effective amount of a Programmed Death (PD)-1 antagonist, a Programmed Death Ligand (PD-L1) antagonist, a Cytotoxic T-lymphocyte-Associated Protein 4 (CTLA-4) antagonist, a B- and T-lymphocyte Attenuator (BTLA) antagonist, T-cell Immunoglobulin and Mucin-domain containing-3 (TIM-3) antagonist, a Lymphocyte-Activation Gene 3 (LAG3) antagonist, or a 4-1BB agonist to the subject. 
     
     
       3. The method of  claim 2 , wherein a) the PD-1 antagonist is an antibody that specifically binds PD-1, or an antigen binding fragment thereof; b) the PD-L1 antagonist is an antibody that specifically binds PD-L1 or an antigen binding fragment thereof; c) the CTLA-4 antagonist is an antibody that specifically binds CTLA-4 or an antigen binding fragment thereof; d) the BTLA antagonist is an antibody that specifically binds BTLA or an antigen binding fragment thereof; e) the TIM-3 antagonist is an antibody that specifically binds TIM-3 or an antigen binding fragment thereof; e) the LAG3 antagonist is an antibody that specifically binds LAG3 or an antigen binding thereof. 
     
     
       4. The method of  claim 3 , wherein the antibody that specifically binds PD-1, the antibody that specifically binds PD-L1, the antibody that specifically binds CTLA-4, the antibody that specifically binds BTLA, the antibody that specifically binds TIM-3 or the antibody that specifically binds LAG3, is a human monoclonal antibody or a humanized monoclonal antibody. 
     
     
       5. The method of  claim 1 , wherein the tumor is a solid tumor. 
     
     
       6. The method of  claim 5 , wherein the solid tumor is a head and neck squamous cell carcinoma, lung cancer, melanoma, ovarian cancer renal cell carcinoma, bladder cancer, cervical cancer, liver cancer, prostate cancer, breast cancer, glioblastoma or rectal cancer. 
     
     
       7. The method of  claim 1 , wherein the CD8 + CD39 + CD103 +  T cells are autologous. 
     
     
       8. The method of  claim 1 , wherein the subject is human. 
     
     
       9. The method of  claim 1 , further comprising resecting the tumor in the subject. 
     
     
       10. The method of  claim 6 , wherein the solid tumor is a melanoma.